rs61739896

chr3-52364681-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015512.5(DNAH1):c.5288C>T(p.Ser1763Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0036 in 1,613,932 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1763S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (77 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (102 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.04

Genes affected

DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058948994).
• BP6: Variant 3-52364681-C-T is Benign according to our data. Variant chr3-52364681-C-T is described in ClinVar as [Benign]. Clinvar id is 478459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.5288C>T	p.Ser1763Leu	missense_variant	33/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.5288C>T	p.Ser1763Leu	missense_variant	34/80
DNAH1	XM_017006130.2	c.5288C>T	p.Ser1763Leu	missense_variant	34/79
DNAH1	XM_017006131.2	c.5288C>T	p.Ser1763Leu	missense_variant	34/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.5288C>T	p.Ser1763Leu	missense_variant	33/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.5549C>T		non_coding_transcript_exon_variant	33/77	2

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2825 AN: 152160 Hom.: 77 Cov.: 33

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00484 AC: 1206 AN: 249056 Hom.: 37 AF XY: 0.00395 AC XY: 534 AN XY: 135138

Gnomad AFR exome AF: 0.0688

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00204 AC: 2976 AN: 1461654 Hom.: 102 Cov.: 31 AF XY: 0.00177 AC XY: 1286 AN XY: 727106

Gnomad4 AFR exome AF: 0.0709

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.00446

GnomAD4 genome AF: 0.0186 AC: 2829 AN: 152278 Hom.: 77 Cov.: 33 AF XY: 0.0180 AC XY: 1343 AN XY: 74454

Gnomad4 AFR AF: 0.0640

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00350 Hom.: 26

Bravo AF: 0.0223

ESP6500AA AF: 0.0562 AC: 227

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00580 AC: 701

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.52
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.17
Sift	Benign	0.067	T
Sift4G	Uncertain	0.0070	D
Vest4		0.64
MVP		0.48
MPC		0.34
ClinPred		0.026	T
GERP RS		4.0
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61739896; hg19: chr3-52398697;